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Managing the late consequences of CHD: What is the evidence for lipid management

Managing the late consequences of CHD: What is the evidence for lipid management. Prof Philip Barter The Heart Research Institute Sydney, Australia. Slides prepared and presented by. 140. 160. 180. 200. 220. 240. 260. 280. 300.

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Managing the late consequences of CHD: What is the evidence for lipid management

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  1. Managing the late consequences of CHD: What is the evidence for lipid management Prof Philip Barter The Heart Research Institute Sydney, Australia Slidesprepared and presentedby

  2. 140 160 180 200 220 240 260 280 300 Serum Cholesterol and CHD in 361,662 US Men: MRFIT 18 16 14 6-Year CHD Death Rate per 1000 Men 12 10 8 6 4 2 0 Serum Cholesterol (mg/dl)

  3. Lipoprotein classes and atherosclerosis Chylomicrons, VLDL, and their catabolic remnants HDL LDL Pro-atherogenic Anti-atherogenic

  4. ROLE OF LDL IN CAUSING ATHEROSCLEROSIS Monocyte Vessel Lumen LDL Endothelium Adhesion Molecule MCP-1 LDL Cytokines MODIFIED LDL Intima Foam Cell Macrophage

  5. Statin Trials: LDL-C Levels vs Events Secondary Prevention 30 4S-Plac 4S-Sim 20 % with CHD event LIPID-Plac LIPID-Pra CARE-Plac CARE-Pra IDEAL-Ator HPS-Plac IDEAL-Sim 10 TNT-Ator10 HPS-Sim TNT-Ator80 0 110 190 70 90 130 150 170 210 LDL-C (mg/dL)

  6. PROVE-IT:Changes From Baseline LDL-C 120 100 Pravastatin 40 mg (Median LDL-C 95 mg/dL) 21%  Median LDL-C (mg/dL) 80 60 Atorvastatin 80 mg (Median LDL-C 62 mg/dL) 49%  40 P<0.001 20 Rand 30 days 4 months 8 months 16 months Final Cannon CP, et al. N Engl J Med. 2004;350:1495-504

  7. 0 30 3 6 9 12 15 18 21 24 27 PROVE-IT: All-cause Mortality or Major CV Events in All Randomized Subjects 30 Pravastatin 40 mg (26.3%) 25 20 % patients with event Atorvastatin 80 mg (22.4%) 15 10 5 16% RRR P=0.005 0 Months of follow-up Cannon CP, et al. N Engl J Med. 2004;350:1495-504

  8. TNT-Study Design • Patient population: • CHD • LDL-C: 130-250 mg/dL (3.4-6.5 mmol/L) • Triglycerides 600 mg/dL (6.8 mmol/L) Primary efficacy outcome measure: • Time to occurrence of a major CV event: • CHD death • Nonfatal, non-procedure-related MI • Resuscitated cardiac arrest • Fatal or nonfatal stroke Baseline Screening and wash-out n=18,469 Open-label run-in n=15,464 Double-blind periodn=10,001LDL-C <130 mg/dL (<3.4 mmol/L) n=5006 Atorvastatin 10 mg Atorvastatin 10 mg LDL-C target: 100 mg/dL (2.6 mmol/L) n=4995 Atorvastatin 80 mg LDL-C target: 75 mg/dL (1.9 mmol/L) 1-8 weeks 8 weeks Median follow-up = 4.9 years

  9. Screen 0 3 12 24 36 48 60 Final TNT-Changes in LDL-C By Treatment Group 160 Baseline 4.0 Atorvastatin 10 mg (n=5006) 140 3.5 Atorvastatin 80 mg (n=4995) 120 3.0 Mean LDL-C level = 101 mg/dL (2.6 mmol/L) 100 2.5 Mean LDL-C (mg/dL) Mean LDL-C (mmol/L) 80 2.0 Mean LDL-C level = 77 mg/dL (2.0 mmol/L) P<0.001 60 1.5 40 1.0 20 0.5 0 0 Study visit (months) LaRosa JC, et al. N Eng J Med. 2005;352

  10. Relative risk reduction = 22% 0 1 2 3 4 5 6 Time (years) TNT-Primary Efficacy Outcome Measure: Major Cardiovascular Events 0.15 HR = 0.78 (95% CI 0.69, 0.89) P=0.0002 Atorvastatin 10 mg Proportion of patients experiencing major cardiovascular event 0.10 Atorvastatin 80 mg 0.05 0 LaRosa JC, et al.N Eng J Med. 2005;352

  11. Relative risk reduction = 25% TNT-Stroke (Fatal or nonfatal) 0.04 HR = 0.75 (95%CI 0.59, 0.96) P=0.02 Atorvastatin 10 mg 0.03 Atorvastatin 80 mg Proportion of patients experiencing fatal or nonfatal stroke 0.02 0.01 0 0 1 2 3 4 5 6 Time (years) LaRosa JC, et al.N Eng J Med. 2005;352

  12. TNT-Primary Endpoint End point No. of patients (%) HR P-value Atorvastatin 10 mg Atorvastatin 80 mg Major CV event 548 (10.9) 434 (8.7) 0.78 0.0002 CHD death 127 (2.5) 101 (2.0) 0.80 0.09 Nonfatal MI 308 (6.2) 243 (4.9) 0.78 0.004 Resuscitated cardiac arrest 26 (0.5) 25 (0.5) 0.96 0.89 Stroke 155 (3.1) 117 (2.3) 0.75 0.02 LaRosa JC, et al. N Eng J Med. 2005;352

  13. TNT-Safety No. of patients (%) Atorvastatin 10 mg (n=5006) Atorvastatin 80 mg (n=4995) Treatment-related AEs Treatment-related myalgia 289 (5.8) 234 (4.7) 406 (8.1) 241 (4.8) Rhabdomyolysis* 3 (0.06) 2 (0.04) AST/ALT elevation >3  ULN 9 (0.2) 60 (1.2) * No cases were considered by the investigator with direct responsibility for the patient to be causally related to atorvastatin, and none met ACC/AHA/NHLBI criteria2 for rhabdomyolysis 1. LaRosa JC, et al. N Eng J Med. 2005;352 2. Pasternak RC et al. Circulation. 2002;106:1024-1028

  14. TNT-Major CVE by on-treatment LDL Quintiles 16 14 12 10 Major CVE (%) 8 6 4 2 0 < 1.6 1.8 2.2 2.5 > 2.7 LDL-C quintile (mmol/L)

  15. TNT-Major CVE by on-treatment LDL Quintiles 16 14 12 10 Major CVE (%) 8 6 4 2 0 < 1.6 1.8 2.2 2.5 > 2.7 LDL-C quintile (mmol/L) La Rosa et al. Am J Cardiol 2007; 100:747-752

  16. TNT-All-cause mortality by on-treatment LDL Quintiles 8 7 6 5 All-cause mortality (%) 4 3 2 1 0 < 1.6 1.8 2.2 2.5 > 2.7 LDL-C quintile (mmol/L) La Rosa et al. Am J Cardiol 2007; 100:747-752

  17. TNT-Non-CV mortality by on-treatment LDL Quintiles 4 3 Non-CV deaths (%) 2 1 0 < 1.6 1.8 2.2 2.5 > 2.7 LDL-C quintile (mmol/L) La Rosa et al. Am J Cardiol 2007; 100:747-752

  18. Cardiovascular Mortality in Secondary Prevention Studies 16 14 12 10 Mortality (%) 8 6 4 2 0 4S (S40) 4S (P) CARE CARE LIPID LIPID (P) HPS HPS (P) TNT TNT (P40) (P) (P40) (S40) (A80) (A10)

  19. Non-cardiovascular Mortality in Secondary Prevention Studies 16 14 12 10 Mortality (%) 8 6 4 2 0 4S (S40) 4S (P) CARE CARE LIPID LIPID (P) HPS HPS (P) TNT TNT (P40) (P) (P40) (S40) (A80) (A10)

  20. Diabetic Subgroup in TNT Shepherd et al, Diabetes Care 2006;29:1220.

  21. Metabolic Syndrome Subgroup in TNT Deedwania et al. Lancet 2006

  22. IDEAL - Protocol Primary • Time to occurrence of a major coronary event • CHD death • Nonfatal MI • Resuscitated cardiac arrest Secondary • Cardiovascular/coronary events • Cerebrovascular events • PAD • Hospitalization with primary diagnosis of CHF • All-cause mortality Open-label period with blinded end point evaluations Patient population • Enrolled at 190 sites throughout Scandinavia and the Netherlands • Diagnosed with CHD • Previous hospitalization with MI, and eligible for statin therapy Atorvastatin 80 mg/day 8888 patients Simvastatin 20 mg/day (titrated to 40 mg if required) 4.8-year follow-up Pedersen et al. Am J Cardiol. 2004;94:720-721; Pedersen et al. JAMA. 2005;294:2437-2445.

  23. 130 120 110 100 90 80 70 0 IDEAL: Effect of Treatment On LDL-C Atorvastatin 3.4 Simvastatin 3.1 Mean LDL-C = 104 mg/dL (2.7 mmol/L) 2.8 LDL-C (mg/dL) 2.6 LDL-C (mmol/L) Mean LDL-C = 81 mg/dL (2.1 mmol/L) 2.3 2.0 1.8 0 Baseline Week 12 Year 1 Year 2 Year 3 Year 4 Year 5 Pedersen et al. JAMA. 2005;294:2437-2445.

  24. 16 16 12 12 8 8 4 4 0 0 40 40 30 30 20 20 10 10 0 0 0 0 0 0 1 1 1 1 2 2 2 2 3 3 3 3 4 4 4 4 5 5 5 5 IDEAL: Composite End Points Major Coronary Event Major Cardiovascular Disease Simvastatin Atorvastatin Cumulative Hazard (%) Cumulative Hazard (%) HR=0.89, P=.07 HR=0.87, P=.02 Years Since Randomization Years Since Randomization Any CHD Any Cardiovascular Disease Cumulative Hazard (%) Cumulative Hazard (%) HR=0.84, P<.001 HR=0.84, P<.001 Years Since Randomization Years Since Randomization Pedersen et al. JAMA. 2005;294:2437-2445.

  25. MIRACL Study Design Patient population Atorvastatin 80 mg • Non-Q-wave infarction or unstable angina • Randomised 24–96 hours from admission • Exclusions: • Planned CABG/PTCA • Prior Q-wave <28 days • CABG <3 months,PTCA <6 months • IIIb/IV CHF • TC >3.1 mmol/L (270mg/dL) 3073patients Usual care + double-blindplacebo 4 months • Primary end point: • Time to ischaemic events (CHD death, non-fatal MI, cardiac arrest, documented angina requiring hospitalisation) Schwartz et al; JAMA. 2001;285:1711-1718.

  26. MIRACL Results Effects on LDL-C: Placebo group 124 mg/dl Atorvastatin group 74 mg/dl Schwartz et al; JAMA. 2001;285:1711-1718.

  27. MIRACL Results Effects on primary endpoint (death, non-fatal MI, cardiac arrest, recurrent ischemia requiring hospitalisation) Placebo group 17.4% Atorvastatin group 14.8% 16% reduction (p< 0.05) Schwartz et al; JAMA. 2001;285:1711-1718.

  28. MIRACL Results Effects on stroke (secondary endpoint) Placebo group 24 Atorvastatin group 12 (p< 0.05) Schwartz et al; JAMA. 2001;285:1711-1718.

  29. MIRACL Conclusion MIRACL provides convincing evidence of the benefits of commencing aggressive LDL lowering very early in patients with acute coronary syndromes Schwartz et al; JAMA. 2001;285:1711-1718.

  30. ARMYDA trial: Study design 7 days 30 days 153 patients Stable Angina Positive stress test Indication to PCI No previous statin treatment Atorvastatin 40 mg/day N=76 PCI Clinical Follow-up Randomization Placebo N=77 1° Blood sample before PCI 2°-3° Blood samples 8 and 24 h post-PCI CK MB, Tn-I, Myoglobin Pasceri et al, 2004; Circulation 110:674-678

  31. Primary end point Incidence of MI, defined as post-PCI increase of CK-MB > 2 times UNL Pasceri et al, 2004; Circulation 110:674-678

  32. ARMYDA trial: Primary end point Post-PCI incidence of myocardial infarction (CK-MB> 2 times UNL) 18 20 P=0.025 15 CK-MB (%) 10 5 5 0 Atorvastatin Placebo Pasceri et al, 2004; Circulation 110:674-678

  33. ARMYDA trial: Conclusions • The ARMYDA randomized trial demonstrates that a short pretreatment with atorvastatin decreases the incidence of myocardial injury during coronary intervention compared with placebo, thereby improving clinical outcome • These results have the potential to influence practice patterns concerning pharmacological therapy prior to percutaneous coronary revascularization Pasceri et al, 2004; Circulation 110:674-678

  34. All statin clinical outcome trials Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events) Number of Events End point Treatment-arm (n=84573) Control-arm (n=84565) Relative risk (95% CI) Any major vascular event 10973 13350 0.78 (0.76-0.80) Any major coronary event 5105 6512 0.75 (0.70-0.82) Any coronary revascularisation 5353 6807 0.71 (0.65-0.78) Any stroke 2302 2680 0.82 (0.74-0.92) CTT Collaborators. Lancet. 2010; 376:1670-1681.

  35. Effects of aggressive vs moderate therapy with statins Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (5 Trials; 39612 subjects; 8,253 events) Number of Events End point Aggressive (n=19829) Moderate (n=19783) Relative risk (95% CI) Any major vascular event 3837 4416 0.72 (0.66-0.78) Any major coronary event 1725 1973 0.74 (0.65-0.85) Any coronary revascularisation 2250 2741 0.66 (0.60-0.73) Any stroke 572 663 0.74 (0.59-0.92) CTT Collaborators. Lancet. 2010; 376:1670-1681.

  36. All statin clinical outcome trials: effects in diabetes Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events) Number of Events Subgroup Treatment-arm (n=84573) Control-arm (n=84565) Relative risk (95% CI) Type 1 diabetes 145 192 0.77 (0.58-1.01) Type 2 diabetes 2494 2920 0.80 (0.74-0.86) No diabetes 8272 10163 0.78 (0.75-0.81) CTT Collaborators. Lancet. 2010; 376:1670-1681.

  37. Aggressive vs moderate statintherapy: effects in diabetes Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (5 Trials; 39612 subjects; 8,253 events) Number of Events Aggressive (n=19829) Moderate (n=19783) Subgroup Relative risk (95% CI) Type 1 diabetes 8 8 0.74 (0.02-22.21) Type 2 diabetes 703 792 0.76 (0.59-0.98) No diabetes 3126 3616 0.71 (0.63-0.80) CTT Collaborators. Lancet. 2010; 376:1670-1681.

  38. All statin clinical outcome trials: effects of baseline LDL-C Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events) Number of Events Baseline LDL-C Treatment-arm (n=84573) Control-arm (n=84565) Relative risk (95% CI) < 2 mmol/L 910 1012 0.78 (0.61-0.99) 2 - 2.5 mmol/L 1528 1729 0.77 (0.67-0.89) 2.5 - 3.0 mmol/L 1866 2225 0.77 (0.70-0.85) 3 - 3.5 mmol/L 2007 2454 0.76 (0.70-0.82) > 3.5 mmol/L 4508 5736 0.80 (0.76-0.83) Heterogeneity trend test: p=0.3 CTT Collaborators. Lancet. 2010; 376:1670-1681.

  39. Aggressive vs moderate therapy: effects of baseline LDL-C Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (5 Trials; 39612 subjects; 8,253 events) Number of Events Baseline LDL-C Treatment-arm (n=84573) Control-arm (n=84565) Relative risk (95% CI) < 2 mmol/L 704 795 0.71 (0.52-0.98) 2 - 2.5 mmol/L 1189 1317 0.77 (0.64-0.94) 2.5 - 3.0 mmol/L 1065 1203 0.81 (0.67-0.97) 3 - 3.5 mmol/L 517 633 0.61 (0.46-0.81) > 3.5 mmol/L 303 398 0.64 (0.47-0.86) Heterogeneity trend test: p=0.2 CTT Collaborators. Lancet. 2010; 376:1670-1681.

  40. All statin clinical outcome trials: effects of gender Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events) Number of Events Subgroup Treatment-arm (n=84573) Control-arm (n=84565) Relative risk (95% CI) Male 8712 10725 0.77 (0.74-0.80) Female 2494 2920 0.80 (0.74-0.86) Heterogeneity trend test: p=0.04 CTT Collaborators. Lancet. 2010; 376:1670-1681.

  41. All clinical outcome trials: effects of duration of treatment Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events) Number of Events Duration (years) Treatment-arm (n=84573) Control-arm (n=84565) Relative risk (95% CI) Year 0-1 3497 3952 0.88 (0.84-0.93) Year 1-2 2112 2645 0.77 (0.73-0.82) Year 2-3 1763 2318 0.73 (0.69-0.78) Year 3-4 1508 1954 0.72 (0.68-0.77) Year 4-5 1224 1486 0.77 (0.72-0.83) Year 5+ 869 995 0.76 (0.69-0.85) CTT Collaborators. Lancet. 2010; 376:1670-1681.

  42. Effects of other subgroups on the ability of statins to reduce major vascular events • No effect of: • Prior vascular disease • Age • Blood pressure • BMI • Smoking • Estimated GFR CTT Collaborators. Lancet. 2010; 376:1670-1681.

  43. All statin clinical outcome trials: effects on Cancer Relative risk of cancer per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol Cancer incidence Comparison Treatment-arm Control-arm Relative risk (95% CI) More vs less statin 5 trials (n=39,612) 1466 1472 1.02 (0.89-1.18) Statin vs Control 21 Trials (n=129,526 3594 3592 1.00 (0.95-1.04) All 26 trials (n=169,138) 5060 5064 1.00 (0.96-1.04) CTT Collaborators. Lancet. 2010; 376:1670-1681.

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